OP0049 AN IMMUNE TARGETED, NON-TOXIC CORTICOSTEROID FOR THE TREATMENT OF SEVERE AUTOIMMUNE DISEASE
Authors: J. Rothstein, K. Bell, C. Carriere, X. Huang, A. Barave, M. Day, A. Kuta, N. Schwertner, S. Seregin
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Glucocorticoids (GC) (aka corticosteroids) are a class of drugs with broad range anti-inflammatory and immunosuppressive activities making them the most potent anti-inflammatory drugs. However, chronic or high dose systemic exposure consistently leads to grievous dose limiting toxicities as in multiple organs including brain, liver and bone.. Altogether, these toxicities prevent GC from being a true panacea in the management of inflammatory diseases particularly in the case of chronic diseases. Targeting GC to immune cells will solve this problem as toxicity mostly occurs in non-immune tissues and cells that are unnecessary for therapeutic efficacy. <h3>Objectives</h3> The objective of INX200 is to give patients a non-toxic glucocorticoid that provides anti-inflammatory efficacy without any glucocorticoid toxicity in a once-per month injection. <h3>Methods</h3> We have achieved specific targeting of GC to the immune system with INX200, an antibody-drug conjugate (ADC). INX200 is a fully humanized immune-targeting monoclonal antibody with silent Fc domain and conjugated through a cleavable linker to budesonide. Validation experiments were conducted using human target knock-in mice, mouse surrogate antibodies and non-human primates in various inflammation and chronic disease models. <h3>Results</h3> We show that INX200 targets both lymphoid and myeloid cells with minimal off-target activity outside the immune compartment. This translates to reduced toxicity when compared to free GC as measured by the lack of impact on the Hypothalamic-Pituitary-Adrenal axis (no changes in corticosterone levels) and bones (no changes in GC- activated transcription) both in mice and non-human primates. INX200 rapidly internalizes allowing for robust and efficient uptake of the ADC thereby providing superior loading of GC into immune cells which results in therapeutic equivalence to free GC at 1/10<sup>th</sup> of the dose. One dose of INX200 also leads to substantially longer exposure (&gt;3 weeks) when compared to free GC (&lt;24h) both in mice and non-human primates. Additionally, we show that in both acute and chronic inflammation models (Figure 1), INX200 is therapeutically as broadly efficacious as free GC demonstrating that GC targeting to immune cells is sufficient for full GC anti-inflammatory efficacy. Finally, developability studies show that INX200 is stable at high concentration and as such suitable for subcutaneous administration. <h3>Conclusion</h3> INX200 retains all the efficacy/potent therapeutic activities of GC but with little to no side effects. The successful targeting of GC to the immune system with the sparing of non-hematopoietic toxicities, offers a transformative advance in GC-based drugs for the treatment of severe, chronic inflammatory diseases such as IBD, lupus and asthma. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.